Inhibition of soluble TNFα prevents adverse atrial remodeling and atrial arrhythmia susceptibility induced in mice by endurance exercise

J Mol Cell Cardiol. 2019 Apr:129:165-173. doi: 10.1016/j.yjmcc.2019.01.012. Epub 2019 Feb 21.

Abstract

Intense endurance exercise is linked to atrial fibrillation (AF). We established previously that interventions that simultaneously interfere with TNFα signaling, mediated via both the enzymatically liberated soluble and membrane-bound forms of TNFα, prevent atrial remodeling and AF vulnerability in exercised mice. To investigate which signaling modality underlies this protection, we treated exercised mice with XPRO®1595, a selective dominant-negative inhibitor of solTNFα. In male CD1 mice, 6 weeks of intense swim exercise induced reductions in heart rate, increased cardiac vagal tone, left ventricular (LV) dilation and enhanced LV function. By contrast, exercise induced hypertrophy, fibrosis, and increased inflammatory cell infiltrates in atria, and these changes were associated with increased AF susceptibility in isolated atria as well as mice, with and without parasympathetic nerve blockade. Although XPRO treatment had no effect on the beneficial physiological changes induced by exercise, it protected against adverse atrial changes as well as AF susceptibility. Our results establish that soluble TNFα is required for exercise-induced increases in AF vulnerability, which is linked to fibrosis, inflammation, and enlargement of the atria, but largely independent of changes in vagal tone.

Keywords: Atrial fibrillation; Exercise; Heart; Inflammation; Tumor necrosis factor alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / complications
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology*
  • Atrial Remodeling* / drug effects
  • Autonomic Nervous System / drug effects
  • Autonomic Nervous System / physiopathology
  • Cardiomegaly / complications
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Electrophysiological Phenomena / drug effects
  • Endurance Training*
  • Fibrosis
  • Heart Atria / drug effects
  • Heart Atria / physiopathology*
  • Heart Rate / drug effects
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Male
  • Mice
  • Physical Conditioning, Animal*
  • Solubility
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Tumor Necrosis Factor-alpha
  • XENP 1595